The present invention relates to an active agent and, in particular, to a proteinase inhibitory agent. More specifically, this invention relates to metalloproteinase inhibitory agent comprising casein-derived peptides.
The degradation of extracellular matrix (ECM) is a very complex process and is part of many pathological and physiological processes. The proteolytic degradation of the extracellular matrix therefore plays a crucial role in cancer invasion as also in non-neoplastic tissue remodeling processes. The role of the matrix-metalloproteinases (MMPs) enzymes in the tumor cell-mediated extracellular matrix proteolysis is well established. Thus, by regulating composition and integrity of ECM, MMPs play an important role in the control of signals elicited by matrix molecules and regulate cell proliferation, differentiation and cell death. MMPs are ubiquitous enzymes and prostate, breast, bone as well as colon tumor cell lines have been shown to secrete MMPs in vitro. The MMP family has over 20 members that cleave various components as various as fibronectin, gelatin and collagen for example. Among the MMPs family, MMP-2 and MMP-9 have been identified in cancer cells and the active forms were detected more frequently in malignant than in benign breast carcinoma. MMP-2 may thus be considered as a key enzyme in ECM remodeling involved in tumor invasion and metastasis.
Beyond cancer and tumor invasion, MMPs are also associated with a wide variety of normal and pathological conditions involving matrix degradation and remodeling. MMPs are thus involved in some physiological processes like foetal development, angiogenesis, bone formation and resorption. Indeed, bone resorption models showed that MMP-9 is specifically required for the invasion of osteoclasts and endothelial cells into the discontinuously mineralized hypertrophic cartilage that fills the core of the diaphysis. MMPs have also been reported to be involved in pathological processes like artherosclerosis, arthritis, autoimmune diseases, periodontitis, tissue ulceration and of course cancer invasion and metastasis.
It is also known that the proteolytic activity of the MMPs involved in ECM degradation may be regulated by their endogenous inhibitors, the tissue inhibitors of metalloproteases (TIMPs). These inhibitors influence the activation of the metalloproteases and act to modulate proteolysis of ECM, notably during tissue remodeling and inflammatory processes. There are also synthetic inhibitors like marimastat for example, a butanediamide derivative with an IC50 in the micromolar range. Inhibitors of MMPs generally fall into three pharmacological categories: collagen peptidomimetics and non-peptidomimetics, tetracyclin derivatives and bisphosphonates.
MMPs inhibitors would therefore have the potential to inhibit tumor growth by preventing local invasion and by inhibiting tumor angiogenesis. The current existing non-endogenous inhibitors present the drawback of a poor oral bioavailability as well as high cost. Moreover since these are synthetic molecules, the synthesis route is generally cumbersome and necessitates purification step in order to recover functional mixtures.
Therefore, there remains a need for a simple procedure for obtaining a metalloproteinase inhibitory agents that would be inexpensive and easy to prepare and that could also be used in a food product or as a neutraceutical additive. The present invention now satisfies this need.